The proposed research is concerned with the investigations related to the determination of (a) the biochemical and the genetic basis of human susceptibility of lung cancer, and (b) the possible use of various enzyme activities in microsomal mixed function oxygenase (MMFO) system in selecting the high risk lung cancer patient. The objectives of the proposed work are to (a) develop sensitive analytical methods for cultured human lymphocytes for assaying various enzyme-catalyzed reactions involved in the metabolic activation and detoxification of polycyclic aromatic hydrocarbons (PAHS), especially those found in cigarette smoke, enzyme activities to be studied include aryl hydrocarbon hydroxylase (AHH) activity, the formation of DNA-binding and water-soluble metabolites and the epoxide hydrase activity; (b) study the genetics of these enzyme activities in a population of healthy humans and cancer patients, especially in lung cancer patients; and (c) determine the correlationships among various activities and with AHH- inducibility in an effort to select an activity or a combination of some of them which would be useful in predicting the susceptibility of humans to lung cancer. The compounds to be studied will include unlabeled and labeled PAHS, such as benzo(a)pyrene, benzo(e)pyrene, dibenz(a, c and a, h) anthracenes, 3-methylcholanthrene, beta-napthoflavone and others. These compounds will be studied as substrates and inducers of the various MMFO and associated activities. Much of the proposed work will be performed with human lymphocytes that have been cultured in the presence of mitogens to transform them into lymphoblasts which have MMFO and associated activites. Particular methods to be used include cell culture, radiochemical and fluorometric techniques, chemical, analytical and synthetic methods, enzymology and other biochemical methods.